The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure (BP) and volume homeostasis. Renin is secreted by the kidney in response to a decrease in circulating volume and blood pressure, and cleaves the substrate angiotensinogen to form the inactive decapeptide Angiotensin I (Ang I). Ang I is converted in the lungs, the kidneys and other organs to form the active octapeptide Ang II by the angiotensin converting enzyme (ACE). Ang II interacts with cellular receptors inducing vascular constriction, the release of catecholamines from the adrenal medulla and pre-junctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. In addition, Ang II inhibits renin release, thus providing a negative feedback to the system. Ang II acts at various levels (e.g. vasculature, sympathetic nervous system, cortex and medulla of the adrenal gland) to increase vascular resistance and BP.
The RAS may be blocked at various levels. Angiotensin II receptor blockers act on the RAS by inhibiting the interaction between Ang II and the AT1 receptor. ACE inhibitors block the conversion of Ang I to Ang II and potentiate bradykinin. Renin inhibitors block the RAS at an earlier point in the cascade than ACE inhibitors and have a different effect on the components of the RAS. After the administration of a renin inhibitor, the formation of both Ang I and Ang II is blocked, thereby preventing the formation of angiotensin peptides by ACE and non-ACE pathways. These effects on the RAS provides the pharmacologic rationale for the study of renin inhibition in hypertension and cardiovascular diseases, and aliskiren (SPP100, SPP100A or SPP100B) is a potent and selective inhibitor of human renin: SPP100A (hydrochloride salt) demonstrated potent in vitro inhibition of human renin (IC50=0.6 nM).
In vivo, SPP100 administered both orally or intravenously in several studies with severely sodium-depleted marmoset monkeys caused complete inhibition of plasma renin activity, sustained reductions in mean arterial pressure and significant increases in plasma concentrations of active and total renin.
A dose ranging study of the effects of Aliskiren and losartan on ambulatory blood pressure monitoring of 4 weeks duration was conducted in patients with mild to moderate hypertension. Dose dependent decreases in blood pressure were observed in the dosage range of aliskiren 75 mg to 300 mg.
An open-label randomized pilot study was conducted comparing the effects of aliskiren versus ramipril on safety, tolerability, BNP (Brain Natriuretic Peptide) and RAAS (Renin Angiotensin Aldosteron System) hormones in patients with NYHA class II-IV heart failure and LVEF <35%. No deleterious effects on hormonal parameters were noted in either group. Trends towards reduced angiotensin II levels were observed in both aliskiren and ramipril groups. PRA was inhibited in the aliskiren group and increased in the ramipril group, in keeping with the different effects of renin and ACE inhibition on PRA.
The renin inhibitor aliskiren (INN name) is chemically 2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide of formula

This compound and its manufacture are specifically disclosed in EP 678503 A.
The active ingredient aliskiren is the free base which is described specifically in EP 678503 A and it has one basic group, the amino group in position 5. This group has a pKa of 9.79 and can thus form salts with acids.
EP 678503 A, discloses the hydrochloride salt (example 137) and the hemifumarate salt (example 83) as specific salts of aliskiren. No crystalline forms are found there.
The oral administration of pharmaceutical agents such as aliskiren as tablets or capsules has certain advantages over parenteral administration such as i.v. or i.m. Diseases requiring treatment with painful injectable formulations are considered to be more serious than those conditions which can be treated with oral dosage forms. However, the major advantage with oral formulations is their suitability for self administration whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel.
Aliskiren hemifumarate is difficult to formulate. Typically, in a galenic formulation comprising aliskiren hemifumarate, a high amount is normally needed of the drug substance (DS) with properties that make the formulation of tablets difficult.
The drug substance quality is very variable with effect on the processability of a tablet, e.g., particle size distribution, bulk density, flowability, wetting behavior, surface area and sticking tendency. Aliskiren hemifumarate known so far is basically amorphous. Moreover, aliskiren is highly hygroscopic. The combination of these hurdles makes a standard tablet manufacturing process extremely difficult.
The low crystallinity, hygroscopicity and relatively low stability, in particular in the presence of moisture, leads to a more complicated manufacturing process in particular when isolating the final product. Specifically processes such as filtration and drying can be very long as a result of the above-mentioned less desirable properties of aliskiren hemifumarate. Aliskiren hemifumarate is also sensitive to the granulation process.
Therefore, despite the very major contribution which aliskiren has made, the reported undesirable properties have been an impediment with respect to the process economy.
Therefore, there is a need for more stable forms of aliskiren, which are even easier to manage in the drying, filtration or granulation processes following the final stage of the chemical preparation process and also in the steps for preparing the pharmaceutical formulations. Many futile attempts have been made to find improved forms through salt formation, the forms ideally being as crystalline as possible, as well as physically and chemically stable.